In the management of many conditions, the regular measurement of analytes in vivo is required. It has been a long-standing objective of both medical science and the military to implant sensors inside the human body that continuously and accurately determine changes in physiologic, metabolic, or fatigue status; measure the concentration of biothreat or therapeutic agents in vivo; and provide early detection of disease prior to the onset of symptoms. Doing so non-invasively with minimal user maintenance is essential, and sensor longevity of months to years is crucial in actual user environments.
For example, measurement of glucose in the blood is essential in order to ensure correct insulin dosing in diabetic patients. Furthermore, it has been demonstrated that in the long term care of the diabetic patient better control of the blood glucose levels can delay, if not prevent, the onset of retinopathy, circulatory problems and other degenerative diseases often associated with diabetes. Thus there is a need for reliable and accurate self-monitoring of blood glucose levels by diabetic patients.
Currently, blood glucose is monitored by diabetic patients with the use of commercially available calorimetric test strips or electrochemical biosensors (e.g. enzyme electrodes), both of which require the regular use of a lancet-type instrument to withdraw a suitable amount of blood each time a measurement is made. On average, the majority of diabetic patients would use such instruments to take a measurement of blood glucose twice a day. However, the US National Institutes of Health recently recommended that blood glucose testing should be carried out at least four times a day, a recommendation that has been endorsed by the American Diabetes Association. This increase in the frequency of blood glucose testing imposes a considerable burden on the diabetic patient, both in terms of financial cost and in terms of pain and discomfort, particularly in the long-term diabetic who has to make regular use of a lancet to draw blood from the fingertips. Thus, there is clearly a need for a better long-term glucose monitoring system that does not involve drawing blood from the patient.
Over the last several decades, many attempts have been made to develop implanted sensors that provide frequent or continuous monitoring. For example, U.S. Pat. No. 4,703,756 to Gough et al. filed May 6, 1986, describes a sensor module for implantation in the body to monitor glucose and oxygen levels. However, due to electrical failure, degradation of the analyte recognition element (typically an enzyme), component degradation and delamination, these sensors typically fail after a relatively short period of time (e.g., hours to days). Another major failure mode of in vivo sensors is not failure of the sensor itself, but rather changes in the tissue immediately adjacent to the sensor due to the implantation of the sensor. The tissue at the interface of the sensor changes in such a way that it is no longer representative of the overall body state or disease state or analyte of interest.
U.S. Pat. No. 7,228,159 describes a sensor comprising a plurality of non-biodegradable sensing particles embedded in a biodegradable matrix for injection into the dermis. However, as the matrix degrades, the sensing particles are ingested by macrophages and removed from the implant site. Similarly, U.S. Pat. No. 6,671,527 describes a sensor which is injected into epidermis and is ejected over time due to the normal sloughing of skin. U.S. Patent Application No. 2009/0131773 describes a carbohydrate (e.g., glucose) sensor made up of at least two different variants of an appropriate competitive binding assay.
Nielsen et al. (2009) J. Diabetes Science and Technology 3(1):98-109, Billingsley et al. (2010) Anal. Chem. 82(9):3707-3713 and McShane et al. (2000) IEEE Engineering in Medicine and Biology Magazine 19:36-45 describe implantation of analyte-sensing microspheres or nanospheres. These individual sensing particles are taken up by macrophages if they are too small, and can migrate through the tissue, which is not desirable for explanation and not desirable to have the fluorescent signal disperse in an uncontrolled way. If the sensing particles are too big to be taken up by macrophages, they undergo the typical foreign body response (FBR), which limits the proximity of capillaries with respect to the implant. As sensors become encapsulated by avascular tissue, they lose ability to accurately sense blood borne analytes and as they become engulfed by phagocytic cells (small particles), they lose contact with interstitial fluid, which is the compartment necessary to be sensed for components such as glucose. Therefore, current sensing technologies typically fail after only a short time in the body (e.g., 2-7 days for commercially available sensors).
Thus, there remains a clear need for sensing technologies that are tissue integrating to provide long-term (e.g., weeks, months or years) and accurate readings by remaining in contact with interstitial fluid (not the internal cellular environment) and remaining in close proximity to the vasculature so that the interstitial fluid surrounding the sensor is in constant rapid equilibrium with nearby capillaries.